Heart failure with reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of the disease is an elevation in sympathetic nervous system (SNS) activity, which manifests peripherally as chronic vasoconstriction. In HFrEF patients, peripheral vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, premature skeletal muscle fatigue, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway. Thus, interventions focused on improving NO bioavailability may offer a new, unexplored strategy for inhibiting SNS overactivity in HFrEF, and thus represent a novel approach for improving and exercise tolerance. To date, studies concerning exercise intolerance in this patient group have failed to provide data linking mechanisms with functional outcomes. Thus, a series of translational studies are proposed to comprehensively quantify the relationship between NO bioavailability and SNS activity in this patient group, and relate these mechanistic findings to the development of exercise intolerance and muscle fatigue in Veterans suffering from HFrEF. Specific Aim 1 will utilize an oral antioxidant (AOx) cocktail to study whether disruptions in oxidative stress can favorably influence exercise tolerance in HFrEF patients. It is hypothesized that chronic AOx administration (Vitamins C [1000mg], E [400 IU], and Alpha Lipoic Acid [600 mg], daily for 8 weeks) will reduce circulating free radical levels, subsequently improving NO bioavailability and inhibiting of SNS activity, which will in turn improve vascular function and exercising limb blood flow. Specific Aim 2 will examine the efficacy of oral tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), to improve exercise intolerance in HFrEF patients. Is it hypothesized that chronic BH4 administration (10 mg/kg daily for 8 weeks) will improve NO bioavailability and inhibit SNS activity, which will in turn improve vascular function and exercising limb blood flow. Specific Aim 3 will examine the therapeutic potential of aerobic, knee-extensor (KE) exercise training to improve skeletal muscle blood flow and thus exercise tolerance in HF patients. Importantly, this exercise modality produces a potent training stimulus without the significant cardiopulmonary stress that accompanies more traditional, whole-body exercise. It is proposed that 12 weeks of supervised KE training will increase NO bioavailability and inhibit SNS activity, which will in turn improve vascular function and exercising limb blood flow. Specific Aim 4 will examine whether the interventional strategies in Aims 1-3 can improve adherence to an 8- week clinical cardiac rehabilitation program. It is hypothesized that chronic AOx consumption (Aim 1), BH4 consumption (Aim 2), and aerobic exercise training (Aim 3) interventions will reduce the rate of attrition from Phase II outpatient Cardiac Rehabilitation in HFrEF patients compared to patients that did not participate in an interventional phase of the study. We anticipate that disrupting this ?vicious cycle? of vasoconstriction in HFrEF may improve overall vascular health to such a degree that significant improvements in exercise-related symptoms are realized, which could therefore improve enrollment in a cardiac rehabilitation program. In this context, findings from the proposed work may provide an important link between vascular and rehabilitative medicine, thus serving to refine current strategies for the treatment of Veterans with HFrEF, ultimately leading to enhanced quality of life in this cohort.